A mild and efficient method for the one-pot monocarboxymethylation of primary amines

Article abstract of DOI:10.1055/s-2007-982531

A mild and efficient method for the monocarboxymethylation of primary amines that takes place under aqueous conditions at room temperature is described. Treatment of an aqueous solution of a variety of primary amines with two equivalents of glyoxylic acid

Full text of DOI:10.1055/s-2007-982531

LETTER
1573
A Mild and Efficient Method for the One-Pot Monocarboxymethylation of
Primary Amines
M
onocarboxym
i
ethylat
m
ion of
P
rimary
A
mi
o
nes thy J. K. Gibbs, Michael Boomhoff, Nicholas C. O. Tomkinson*
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20874030; E-mail: tomkinsonnc@cardiff.ac.uk
Received 23 January 2007
tion. Within this letter we report a mild and efficient route
for the conversion of primary amines to their N-formyl
glycine and glycine analogues, expand the scope of the
transformation and describe the application of this proce-
Abstract: A mild and efficient method for the monocarboxymeth-
ylation of primary amines that takes place under aqueous conditions
at room temperature is described. Treatment of an aqueous solution
of a variety of primary amines with two equivalents of glyoxylic
acid leads to the N-formyl glycine derivatives. Direct hydrolysis of dure to the reaction of diamines.
the crude reaction solution leads to the products of amine mono-
carboxymethylation in good to excellent yield.
glyoxylic acid (3)
CH2Cl2, r.t.
O
O
N
N
Key words: metal-free synthesis, amino acids, glycine derivatives
H
CO2H
x
N
H
Bn
Bn
NH2
2
1
The development of robust synthetic methods of broad
utility is of primary concern. Within this context, addition
to existing methodology that results in cheaper, more
efficient and convenient processes provides the driving
force behind much research.
glyoxylic acid (3) (2 equiv)
CH2Cl2, r.t.
CHO
N
O
NH
N
CO2H
Small organic molecules containing amides and peptido-
mimetics represent a fundamental class of bioactive com-
pound of which N-alkylated glycine derivatives are an
important subsection.1 The most widely method used for
the introduction of N-alkyl glycines is the alkylation of
primary amines with a-halo acids and esters.2 Although
well developed, the reaction frequently suffers from prob-
lems of overalkylation which can be circumvented by the
addition of excess amine or the acceptance of poor yields.
Pr
5
Bn
CO2H
CHO
4
Scheme 1 Attempted synthesis of imidazolidinone 2
Initial optimisation studies were conducted on the reac-
tion between phenethylamine (6) and glyoxylic acid (3,
Table 1). The reaction was reasonably efficient in a broad
spectrum of reaction solvents over the 24 hour period (en-
tries 1–7), with the optimal solvent being water (entry 8).
Stirring one equivalent of phenethylamine (6) with two
equivalents of glyoxylic acid monohydrate (3) at room
temperature for 24 hours cleanly gave the N-formyl ad-
duct 7 in 75% isolated yield. Although water is frequently
cited as a ‘green’ solvent (even when large quantities of
organic solvents are often used in compound isolation and
purification), we believe the specific advantage of using
an aqueous environment for this transformation is that it
allows for the direct one-pot conversion to the synthetical-
ly useful N-alkyl glycine derivative 8 without isolation of
the formylated intermediate 7. Thus, addition of 2 M HCl
directly to the crude reaction mixture and heating the re-
sulting solution for five hours led to 8 which could easily
be isolated by crystallisation (entry 9). The reaction se-
quence was equally effective using 1 M aqueous glyoxylic
acid solution to prepare both the intermediate 7 (entry 10,
77%) and the glycine derivative 8 (entry 11, 69%).
Within an ongoing project concerned with the discovery
of efficient molecular scaffolds for amino catalytic
transformations3 we reacted the amino amide 1 with one
equivalent of glyoxylic acid (3) in dichloromethane at
room temperature with the aim of preparing the imidazo-
lidinone 2 (Scheme 1).4 This reaction failed to deliver the
expected product, the N-formyl glycine derivative 4 being
isolated in 38% yield (together with unreacted starting
material 1). Conducting the reaction in the presence of
two equivalents of glyoxylic acid gave 4 in 74% yield. An
exhaustive search of the literature revealed an isolated
report of this class of transformation for the reaction of
primary amines with glyoxylic acid using either trifluoro-
acetic acid or formic acid as the reaction solvent.5 For
example, reaction of propylamine with 2.05 equivalents
of glyoxylic acid at 70 °C for 14 hours gave the N-formyl
derivative 5 in 93% isolated yield. Although efficient, we
believed our conditions were significantly milder than
those previously reported and warranted further examina-
Having developed mild and efficient conditions for the
one-pot carboxymethylation of phenethylamine we went
on to examine some of the scope of the transformation.6
SYNLETT 2007, No. 10, pp 1573–1576
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982531; Art ID: D02207ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.0
6
.2
0
0
7

1574
T. J. K. Gibbs et al.
LETTER
Table 1 Examination of Solvent Systemsa
Table 2 Scope of the Transformationa
CO2H
HCl
(2 M)
NH2
CO2H
CHO
NH2
NH2
4-BrPh
NH2
nBu
Bn
solvent, 3
Cy
NH2
Ph
NH
N
9
10
11
12
r.t., 24 h
·HCl
∆, 5 h
Ph
Ph
8
6
7
HO2C
NH2
NH2
4-MeOPh
13
NH2
Entry
Solvent
CH2Cl2
Et2O
Conversion (%)
14
17
15
1
2
72e
49d
64d
23d
45d
43d
30d
75d
70e
77d
69e
CO2H
Et3N
H
N
NH2
16
3
EtOAc
MeOH
MeCN
PhMe
THF
18
4
Entry
1
Amine
Product
Yield (%)
78
5
⋅HCl
6
H
N
CO2H
9
nBu
7
19
8
H2O
⋅HCl
H
N
CO2H
CO2H
9c
10b
11b,c
H2O
2
10
86
Cy
20
H2O
⋅HCl
H2O
H
N
3
4
5
6
11
12
13
14
79
60
68
25
Bn
a All reactions performed at r.t. for 24 h at 0.2 M concentration using
glyoxylic acid monohydrate unless otherwise stated.
b Reaction conducted using commercial 1 M glyoxylic acid solution.
c Isolated yield of 2-(phenylethylamino)acetic acid (8).
d Determined from 1H NMR of crude reaction mixture.
e Isolated yield.
21
⋅HCl
H
4-BrPh
N
CO2H
22
⋅HCl
H
4-MeOPh
N
CO2H
23
The reaction was equally efficient with primary and
secondary a-substitution of the reactive nitrogen (entry 1,
78%; entry 2, 86%) suggesting a broad range of substitut-
ed amines will participate in the process. Benzylic sub-
strates were also efficient (entry 3, 79%) with electron-
donating and -withdrawing substitution on the aromatic
ring also being tolerated (entry 4, 60%; entry 5, 68%).
Functional groups such as alkenes (entry 6, 25%) and
carboxylic acids (entry 7, 54%; entry 8, 77%) are also per-
mitted.
⋅HCl
H
N
CO2H
24
HO2C
N
H
⋅HCl
CO2H
7
8
15
16
54
77
25
CO2H
N
CO2H
The precise mechanism by which the reaction proceeds is
unclear at present; a possible mechanism explaining the
observed outcome is outlined in Scheme 2. From the stoi-
chiometry of the reaction (2 equiv glyoxylic acid) it is not
possible for the glyoxylic acid to act as a hydride source
in an analogous manner to formic acid in the reductive
amination of aldehydes.7 This suggests the imine 28, re-
sulting from the condensation of the amine 27 with glyox-
ylic acid (3), adds to a second molecule of glyoxylic acid
to give the intermediate 29. The ensuing decarboxylation
would then lead to the observed product 31 after protona-
tion. Imines derived from the reaction of primary amines
and glyoxylic acid are well known and characterised8 and
have been exploited as reactive intermediates in tandem
reaction processes including the Diels–Alder reaction9
and nucleophilic additions of nitro alkanes.10 The action
H
⋅HCl
26
9
17
18
no reaction
–
–
10
no reaction
a All reactions performed at r.t. for 24 h at 0.2 M concentration using
glyoxylic acid monohydrate followed by addition of 2 M HCl and
heating for 5–18 h.
of imines as nucleophiles is less frequently utilised as a
synthetic technique, although is well established in, for
example, N-acyliminium chemistry.11
Within the examination of the scope of the reaction we
confirmed that both secondary (Table 2, entry 9) and ter-
tiary amines (Table 2, entry 10) were returned unreacted
Synlett 2007, No. 10, 1573–1576 © Thieme Stuttgart · New York

LETTER
Monocarboxymethylation of Primary Amines
1575
Table 3 Reaction of Diaminesa
R
+
N
R
O
OH
NH2
N
CO2H
NH2
NH2
H
N
NH2
–O
O
N
H
27
28
NH2
H2N
OH
29
–CO2
32
33
34
35
36
N
N
NH2
R
OH
+
N
Entry
1
Amine
Product
Yield (%)
41
R
+ H+
N
CO2H
O–
OH
⋅2HCl
CHO
31
H
N
CO2H
CO2H
30
32
N
H
Scheme 2 Possible mechanism for the observed transformation
37
⋅2HCl
H
N
after exposure to the standard reaction conditions. This
opened the possibility to react a series of diamine sub-
strates that would further exemplify the strength of the
methodology. In the alkylation of diamines using alkyl
halides, selective functionalisation of a primary amine in
the presence of either a secondary or tertiary amine is
difficult and frequently relies on protecting-group strate-
gies.12 The current work allows for chemospecific reac-
tion of a primary amine in the presence of both secondary
and tertiary amines (Table 3). For example, reaction of N-
methylethylenediamine (32) with glyoxylic acid monohy-
drate (3) at room temperature followed by addition of 2 M
hydrochloric acid and refluxing the resulting solution for
18 hours led to the glycine derivative 37 in 41% isolated
yield. The protocol was equally effective for the diamines
33–35 giving the corresponding monocarboxymethylated
products 38–40 in 44–68% yield (Table 3, entries 2–4).
The monocarboxymethylated derivative of ethylenedi-
amine 41 has been used by Bradley in the preparation of
PNA–peptide conjugates.13 This was prepared by the ad-
dition of a large excess of ethylenediamine (10 equiv) to
a-bromoacetic acid.14 A more convenient access to this
compound can be achieved using one equivalent of ethyl-
enediamine 36 and glyoxylic acid monohydrate (3) which
gave the monocarboxymethylated adduct in 31% isolated
yield after crystallisation of the product from methanol
(Table 3, entry 5).
2
33
N
68
38
⋅2HCl
H
N
H
N
CO2H
CO2H
CO2H
3
4
34
35
44
59
39
⋅2HCl
H
N
N
40
⋅2HCl
H
N
5
36
31
H2N
41
a All reactions performed at r.t. for 24 h at 0.2 M concentration using
glyoxylic acid monohydrate followed by addition of 2 M HCl and
heating for 5–18 h.
Typical Experimental Procedure for the Monocarboxy-
methylation of Primary Amines
Glyoxylic acid monohydrate (3, 1.52 g, 16.5 mmol) was dissolved
in distilled H2O (40 mL) at r.t. Phenethylamine (6, 1.00 g, 8.25
mmol) was added and the resulting solution stirred for 24 h. During
this time the formation of a white precipitate was observed. After
this period 2 M HCl (20 mL, 40 mmol) was added and the reaction
mixture heated at reflux overnight. The solvent was removed under
reduced pressure and the residue recrystallised from MeOH–Et2O
to give 2-(phenylethylamino)acetic acid hydrochloride (8, 1.24 g,
70%) as a colourless solid; mp 184 °C. IR (Nujol): 2924, 1748 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 13.80 (br s, 1 H), 9.38 (br s, 2
H) 7.36–7.24 (m, 5 H), 3.89 (s, 2 H), 3.16 (t, J = 10.0 Hz, 2 H), 2.99
(t, J = 10.0 Hz, 2 H). 13C NMR (125 MHz, DMSO-d6): d = 168.5
(s), 137.6 (s), 129.1 (d), 129.1 (d), 127.3 (d), 48.1 (t), 47.3 (t), 31.8
(t). MS (ES): m/z = 180 [M + H – HCl]+. HRMS (ES): m/z calcd for
C10H14N1O2 [M + H – HCl]+: 180.1025; found: 180.1019.
In summary, we have developed a simple one-pot proce-
dure for the monocarboxymethylation of primary amines.
The reaction is operationally simple and applicable to a
broad range of substrates. Significantly, the reaction does
not work on secondary amines and thus allows for the
chemospecific reaction of unprotected diamines, which is
not the case for alternative methods for this class of bond
construction. All the products reported were easily crys-
tallised from methanol–diethyl ether, greatly simplifying
the experimental protocol. We are currently investigating
the application of this methodology to the construction of
piperazinones and will report on our findings shortly.
Acknowledgment
The authors thank Professor David Knight for insightful discussi-
ons, the EPSRC for a fellowship (N.C.O.T.), and financial support
(T.J.K.G.) and the Mass Spectrometry Service, Swansea for high-
resolution spectra.
Synlett 2007, No. 10, 1573–1576 © Thieme Stuttgart · New York

1576
T. J. K. Gibbs et al.
LETTER
(6) All compounds prepared were characterised by mp, 1H
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Synlett 2007, No. 10, 1573–1576 © Thieme Stuttgart · New York